Method and composition for treating rhinitis

ABSTRACT

A pharmaceutical composition for the treatment of rhinitis by nasal or ocular administration comprises zwitterionic cetirizine, polar lipid liposome, a pharmaceutical acceptable aqueous carrier and, optionally, a pharmaceutically acceptable buffer capable of providing a pH of from pH 4.0 to pH 8.0, with the proviso that, if the polar lipid comprises phospholipid, the amount of phospholipid in the composition from is from 10 mg per mL to 120 mg per mL. Also disclosed are methods for its preparation and methods for treating rhinitis by its nasal or ocular administration.

FIELD OF THE INVENTION

The present invention relates to a method for treating rhinitis, and toa corresponding pharmaceutical composition.

BACKGROUND OF THE INVENTION

Allergic and non-allergic rhinitis are common disorders affecting about30% of the population. Rhinitis does have considerable impact on qualityof life. In fact, rhinitis is regarded to affect the quality of life,even more so than, e.g., asthma.

Hay fever and perennial allergic rhinitis are characterised by sneezing,rhinorrhea, nasal congestion, pruritus, conjunctivitis and pharyngitis.In perennial rhinitis, chronic nasal obstruction is often prominent andmay extend to eustachian tube obstruction. Oral or local antihistaminesare first line treatment, and nasal steroids second line treatment forrhinitis. For most patients, topical corticosteroids and long actingantihistamine agents provide significant relief of symptoms.Antihistamines may also affect non-immunologically (non-IgE) mediatedhypersensitivity reactions such as non-allergic rhinitis, exerciseinduced asthma, cold urticaria, and non-specific bronchialhyperreactivity.

Cetirizine dihydrochloride,[2-{4-[(4-chlorophenyl)-phenylmethyl]-1-piperazinyl-}ethoxy]acetic acidis an orally and locally active, potent, long acting peripheralhistamine H₁ receptor antagonist. Cetirizine is one of the most widelyused second generation antihistamines for the treatment ofrhino-conjunctivitis and urticaria. It is effective, well tolerated, andsafe when used orally in a dose of 10 mg daily. Sedation and dry mouthdo however occur as side effects in orally treated patients. Cetirizineis also approved in children for the treatment of rhinitis.

The main clinical affects of antihistamines include reduced sneezing andrhinorrhea, while nasal blockage is less responsive. Localadministration of antihistamines (azelastine and levocabastine) hasadvantages, such as rapid onset of action and fewer side effects. Atpresent cetirizine dihydrochloride is not an approved medicine for localadministration, although it has been administered in that manner inclinical trials.

Some effect was seen on symptoms when cetirizine (presumably asdi-hydrochloride) was given as a nasal spray in patients with perennialallergic rhinitis. Concentrations of 0.625, 1.25, and 2.5 mg/mL ofcetirizine were sprayed three times a day for two weeks (Clement P,Roovers M H, Francillon C, Dodion P. Dose-ranging, placebo-controlledstudy of cetirizine nasal spray in adults with perennial allergicrhinitis. Allergy September 1994; 49(8):668-72). The most common sideeffects were related to nasal events, though no difference in incidencebetween the placebo and the cetirizine-treated groups were seen.However, the authors speculate that local irritation had an adverseeffect on treatment efficacy. In another trial (Francillon C, Pécoud A.Effect of nasal spray of cetirizine in a nasal provocation test withallergen. J Allergy Clin Immunol 1993:91, Suppl 2:258 (abstract)),cetirizine nasal spray was found to reduce symptoms and increase nasalpeak flow after an allergen challenge. In exercise-induced asthma, agood protective effect was seen when cetirizine mist was administered tothe lung with a nebulizer (Ghosh S K, De Vos C, McIlroy I, Patel K R.Effect of cetirizine on exercise induced asthma. Thorax April 1991;46(4):242-4).

Due to the irritation of the nasal mucosa by cetirizine it is necessaryto decrease its immediate exposure of the drug in nasal administration.It has been reported that this can be achieved by providing cetirizinein form of a composition containing cyclodextrin (EP 0 605 203 B1).

The lipophilicity behaviour of the cationic (anion: chloride),zwitterionic, and anionic forms of cetirizine in buffered aqueousphosphatidylcholine liposome systems containing from about 1 to 33.5mg/mL of phospholipid has been studied (Plemper van Balen G et al.Lipophilicity behaviour of the zwitterionic antihistamine cetirizine inphosphatidylcholine liposomes/water systems. Pharm. Res. 2001;18:694-701. The aim with the study was to gain insight into themechanism of interaction of the various electrical species of cetirizinewith membranes. In respect of the cationic species, both hydrophobic andelectrostatic interactions were found to be involved. The authorsconsider the zitterionic form of cetirizine, which dominates in the pHrange of from about pH 4 to about pH 7, and even from about pH 3 toabout pH 8, to be prevented from entry into the liposomal membrane byrendering the formation of lipophilic folded conformers of cetirizinemore difficult.

OBJECTS OF THE INVENTION

It is an object of the present invention to provide a pharmaceuticalcomposition for nasal administration of cetirizine that protects thenasal mucosa from irritation by the active agent.

It is another object of the present invention to provide apharmaceutical composition for ocular administration of cetirizine thatprotects the ocular mucosa from irritation by the active agent.

Still another object of the present invention is to provide a processfor the manufacture of this composition.

An additional object of the invention is to provide a method for thetreatment of rhinitis by nasal administration of cetirizine which lacksat least some of the drawbacks of known methods.

Further object of the invention will become apparent from the study ofthe following summary of the invention, the description of preferredembodiments thereof, and the appended claims.

SUMMARY OF THE INVENTION

The present invention is based on the finding that the presence ofliposomes in an aqueous cetirizine solution of a pH at which itszwitterionic form predominates, such as a pH from about pH 4 or pH 5 toabout pH 7 and even pH 8, reduces or even eliminates irritation of thenasal mucosa or the ocular mucosa caused by the drug.

According to the present invention is disclosed a pharmaceuticalcomposition for the treatment of rhinitis by nasal or ocularadministration comprising zwitterionic cetirizine, polar lipid liposome,a pharmaceutical acceptable aqueous carrier and, optionally, apharmaceutically acceptable buffer capable of providing a pH of from pH4 to pH 8, preferably from pH 5.0 to pH 7.0, with the proviso that, ifthe polar lipid comprises phospholipid, the amount of phospholipid inthe composition from is from 10 or 17 mg to 120 mg per mL, morepreferred from 35 mg to 70 mg per mL.

Any pharmaceutically acceptable salt of cetirizine as well as thezwitterionic form thereof can be used in the invention. Particularlypreferred is the use of nitrate salts of cetirizine, most preferred ofcetirizine dinitrate.

It is preferred for the composition of the invention to comprisecetirizine or a salt of cetirizine in an amount of from 1 mg/mL to 23mg/mL calculated on the zwitterionic form, preferably in an amount offrom 5.5 mg/mL to 22 mg/mL.

The composition of the invention can be administered as a nasal spray,nasal drops, and eye drops. It is also possible to administer it as afine mist to the lungs by nebulization. Irrespective of administrationroute the irritating properties of cetirizine are reduced by thecomposition of the invention.

Liposomes are well known in the art. A liposome is a structureconsisting of one or more concentric spheres of lipid bilayers separatedby water or aqueous buffer compartments.

Numerous patents and scientific papers on liposomes have been publishedand the technical field of applying various lipid derivatives incombination with amphiphatic compounds such as phospholipids are wellknown to those skilled in the art. Liposomes can be prepared by variousmethods using solvents, reduced pressure, two-phase systems, freezedrying, sonication etc. described, for instance, in Liposome DrugDelivery Systems, Betageri G V et al., Technomic Publishing AG, Basel,Switzerland, 1993, which is incorporated herein by reference.

Liposomes may be based on phospholipids, in particularphosphatidylcholine (PC), phosphatidylglycerol (PG),phosphatidylinositol (PI), phosphatidic acid (PA), phosphatidylserine(PS), or mixtures thereof.

The phospholipids of the invention comprise polar and non-polar groupslinked to a backbone entity carrying hydroxyl groups, such as glycerol.According to a preferred embodiment of the invention the phospholipid isof natural origin, preferably membrane phospholipid. According toanother preferred embodiment of the invention the phospholipid is ofsynthetic or semi-synthetic origin.

Phospholipids can be represented by the general formula I

wherein R₁ and R₂ independently represent a saturated or unsaturated,branched or straight chain alkyl or alkylene group having 7-23 carbonatoms, preferably 11-19 carbon atoms; and R₃ represents an amide orester bonding group, such as —CH₂—CHOH—CH₂OH (phosphatidylglycerol),—CH₂—CH₂—CH₂—N(CH₃)₃ (phosphatidylcholine), —CH₂—CH₂—NH₂(phosphatidylethanolamine), H (phosphatidic acid), —CH₂—CH(NH₂)—COOH(phosphatidylserine).

Particularly preferred phospholipids are those swelling in water, whichare capable of spontaneous liposome formation. For a phospholipid toform a liposome in excess of water it is necessary that a lamellarliquid crystalline phase is formed, as with phosphatidylcholine (PC).Phosphatidylethanolamine (PE) on the other hand normally favours thereversed hexagonal phase.

If the phospholipid of the invention does not swell spontaneously inwater, it is nevertheless possible to obtain liposomes from it by addinga more polar, swellable phospholipid, such as an anionic phospholipid,preferably phosphatidylglycerol.

The liposome formation can be performed at room temperature or any othertemperature above 0° C. if the phase transition temperature of the acylchains (chain melting; gel-to-liquid crystals) is below the freezingpoint of water, which is the case for natural phospholipids.

According to a first preferred aspect of the invention the polar lipidcomprises or, more preferred, consists of glycolipid. In thisapplication, the term glycolipid designates a compound containing one ormore monosaccharide residues bound by a glycosidic linkage to ahydrophobic moiety such as an acylglycerol, a sphingoid or a ceramide(N-acylsphingoid).

According to a second preferred aspect of the invention glycolipid is aglycoglycerolipid. In this application the term glycoglycerolipiddesignates a glycolipid containing one or more glycerol residues.According to a particularly preferred aspect of the inventionglycoglycerolipid comprises or consists of galactoglycerolipid,preferably digalactosyldiacylglycerol of the general formula (II)

R₁ and R₂ having the same meaning as in general formula (I).

According to a third preferred aspect of the invention glycolipid is aglycosphingolipid. In this application the term glycosphingolipiddesignates lipids containing at least one monosaccharide residue andeither a sphingoid or a ceramide. Glycosphingolipid comprises neutralglycophingolipids such as mono- and oligoglycosylsphingoids as well asmono- and oligoglycosylceramides. Most preferred are the respective monoforms. Glycosphingolipid additionally comprises acidicglycosphingolipids such as sialoglycosphingolipids,uronoglycosphingolipids, sulfoglycosphingolipids,phosphoglycosphingolipids, and phosphonoglycosphingolipids. Theglycosphingolipid can be ceramide, monohexosylceramide,dihexosylceramide, sphingomyelin, lysosphingomyelin, sphingosine, ormixtures thereof. Preferably the glycosphingolipid is sphingomyelin orproducts derived from sphingomyelin. The sphingomyelin content ispreferably established by chromatographic methods. Sphingomyelin can beextracted from milk, preferably bovine milk, brain, egg yolk orerythrocytes from animal blood, preferably sheep. Synthetic andsemi-synthetic sphingolipids are comprised by the invention.

According to a fourth preferred aspect of the invention glycolipid is aglycophosphatidylinositol. In this application the termglycophosphatidylinositol designates glycolipid which containssaccharides glycosidically linked to the inositol moiety ofphosphatidylinositols.

The composition of the invention may also comprise antioxidant.Antioxidants of the invention comprise alpha tocopherol, ascorbic acid,butylated hydroxyanisole, butylated hydroxytoluene, citric acid, fumaricacid, malic acid, monothioglycerol, propionic acid, propyl gallate,sodium ascorbate, sodium bisulfite, sodium metabisulfite, potassiummetabisulfite, sodium sulfite, tartaric acid, and vitamin E.

The buffer of the invention is a pharmaceutically acceptable buffer ofany kind that does not interfere with the formation of liposomes, suchas a phosphate, citrate, or acetate buffer, and which is capable ofmaintaining a pH of from about pH 4 to about pH 8 or from about pH 5.0to about pH 7.0.

According to the invention a chelating agent may be used to reduce themetal ion catalysed oxidation of phospholipid and/or cetirizine.Examples of useful chelating agents are ethylenediaminetetraacetic acid(EDTA), ethylenediaminetriacetic acid and diethylenetriaminepentaaceticacid (DTPA). It is also possible to use other agents that protect thecomposition of the invention and, in particular, possible unsaturatedfatty acid residues therein, from oxidation.

The composition of the invention can comprise one or more preservatives.Examples of common preservatives for liquid pharmaceutical compositionsare benzalkonium chloride, benzoic acid, butylated hydroxyanisole,butylparaben, chlorbutanol, ethylparaben, methylparaben, phenoxyethanol,and phenylethyl alcohol.

To retain the composition of the invention at its application site itcan also comprise viscosity-increasing agent such as, for instance,hydrophilic polymers like polyethyleneglycol, cellulose derivatives suchas hydroxypropylmethyl cellulose.

Buffering agents, preservatives, viscosity-increasing agents,anti-oxidants, chelating agents and other optional additives will beselected keeping in mind that their detrimental effect on liposomestability should be kept at a minimum. For a given agent this can beascertained by simple experiments, which are within the reach of aperson skilled in the art.

According to the invention is also disclosed a process for preparing acomposition of the aforementioned kind. Preferably the liposome of theinvention is prepared by direct swelling of the compound in an aqueousmedium without adding any other substances such as stabilizers etc.which are normally required.

In particular, according to the present invention, is disclosed aprocess for preparing a pharmaceutical composition for the treatment ofrhinitis by nasal or ocular administration comprising zwitterioniccetirizine, polar lipid liposome, a pharmaceutical acceptable aqueouscarrier and, optionally, a pharmaceutically acceptable buffer capable ofproviding a pH of from about pH 4 to about pH 8, preferably from aboutpH 5.0 to about pH 7.0, with the proviso that, if the polar lipidcomprises phospholipid, the amount of phospholipid in the composition isfrom 10 or 17 mg to 120 mg per mL, more preferred from 35 mg to 70 mgper mL, comprising

-   -   (a) providing a polar lipid or a mixture of polar lipids that is        swellable in aqueous media;    -   (b) providing an aqueous solution of cetirizine and buffer        having a pH of from pH 4 to pH 8;    -   (c) adding the polar lipid to the aqueous solution while        stirring, thereby forming a cetirizine liposome preparation;    -   (d) optionally adjusting the pH of the preparation to a desired        value within the range of from pH 4 to pH 8 by adding an acid or        a base;    -   (e) optionally adding water or saline to the preparation to        obtain a desired final batch volume;    -   (f) homogenising the preparation to obtain said pharmaceutical        composition.

A preferred aqueous medium is a buffered aqueous solution of cetirizine.Useful buffers are those capable of buffering at a pH within the rangefrom pH 4 to pH 8, more preferred from about pH 5.0 to about pH 7.0, andcomprise phosphate buffer, citrate buffer, acetate buffer. The personskilled in the art is aware of the inherent buffering effect ofzwitterionic cetirizine.

The formation of the liposomes of the invention is facilitated by thespontaneous swelling the polar lipid in water forming a lamellar liquidcrystalline phase having a maximum water content of about 35% by weight.Depending on the lipid or lipid mixture used and the other conditions aspontaneous formation of liposomes can be obtained when water is addedto this lamellar phase. If spontaneous formation is not obtained, theformation of liposomes can be accomplished by mechanical dispersion ofthe lamellar liquid-crystalline phase in excess water.

A preferred dispersion method is vigorous mechanical mixing by, forinstance, high speed homogenisation, such as by means of an UltraTurrax® (Jankel & Kühnke, Germany) homogeniser, but shaking, vortexingand rolling can also be performed.

A homogeneous size distribution of the liposomes of the invention isdesirable. It can be obtained by extrusion through a membrane filter,such as one made of polycarbonate, with a pore size of 100 nm. Membranefilters for use in the invention can be procured from Avestin Inc.,Canada. A reduced average liposome size and narrowed liposome sizedistribution is also obtained when the liposomal dispersion is subjectedto high-pressure homogenisation with a suitable homogeniser (Rannie A PV, type 7.30 VH, Rannie A S, Denmark) at 500 bar for 4-6 cycles.

Surprisingly it was found that the presence of cetirizine in a liposomevehicle resulted in a reduction of liposome size. Smaller liposomes aregenerally more stable physically and, due to their higher surface/volumeratio, easier resorbed by the mucosa.

The preparation of the composition according to the invention does notnormally require conventional treatment with organic solvents such aschloroform or dichloromethane. However, if two or more membrane lipidsare used it may be necessary to treat them with organic solvent prior tothe addition of the aqueous solvent.

According to the present invention is also disclosed a method fortreating rhinitis comprising the nasal administration of apharmacologically effective amount of the composition of the inventionto a person suffering from rhinitis. For nasal administration anystate-of-the-art devices suitable for producing sprays of aqueousliposomal dispersions can be used. It is also possible to administer thecomposition of the invention by nasal drops and even by inhalation ofcetirizine liposome mist from a nebulizer. A corresponding method oftreatment according to the invention by ocular administration is alsodislosed. Preferably the composition of ocular administration is in theform of eye drops.

According to the present invention is furthermore disclosed a method forthe manufacture of a pharmaceutical composition for the treatment ofrhinitis by nasal or ocular administration comprising cetirizine and apharmacologically acceptable liposomal carrier comprising polar lipiddispersed in an aqueous medium with the proviso that, if the polar lipidcomprises phospholipid, the amount of phospholipid in the composition isfrom 10 mg or 17 mg per mL to 120 mg per mL, more preferred from 35 mgper mL to 70 mg per mL.

In the following the invention will be explained in more detail byreference to a number of preferred embodiments.

DESCRIPTION OF PREFERRED EMBODIMENTS MANUFACTURE OF EXEMPLARYCOMPOSITIONS OF THE INVENTION (EXAMPLES 1-4) EXAMPLE 1

TABLE 1 Batch formula of the composition of the invention Cetirizinedinitrate* 22.2 g Phospholipid (from soybean**) 70.0 g Disodiumphosphate dihydrate; Na₂HPO₄.2H₂O 21.3 g Potassium dihydrogenphosphate;KH₂PO₄ 11.0 g 1 M Hydrochloric acid and/or 1 M sodium hydroxide to pH7.0 Water for injection to 2.0 L*White solid, crystallized from THF/acetonitrile/water 2:1:0.28.Obtained from commercially available cetirizine dihydrochloride vianeutralisation of the free base with nitric acid.**Lipoid S75, Lipoid GmbH, Germany

General procedure. For weights and volumes reference is made to Table 1.A buffer solution is prepared by dissolving the buffering agentsdisodium phosphate dihydrate (Na₂HPO₄.2H₂O) and potassium dihydrogenphosphate (KH₂PO₄) in 1600 ml water (80% of the total batch volume) in a2000 mL volumetric flask. The weighed amount of active agent is added tothe buffer solution and dissolved by stirring with a magnetic stirrer,followed by addition of 100 ml aqueous 1 M sodium hydroxide. Thephospholipid is separately weighed and added to the cetirizine solution.Stirring is continued until a well dispersed suspension has been formed,the pH of which is adjusted to pH 7.0±0.1 with 1.0 M NaOH or 1.0 M HCl.The volume of the preparation is then brought to the final batch volumeof 2000 mL. The preparation is transferred to a 5 L glass vesselprovided with an Ultra Turrax® T25 homogeniser (Jankel & Kühnke,Germany). Homogenisation is carried out at 22000 rpm for 3×2 minutesinterrupted by 10 min settling periods. 10 mL aliquots of the thusobtained composition of the invention are removed from the stirreddispersion and transferred to glass vials onto which spray heads (VP7 orVP7D; Valois S. A., France) are either crimped on or attached by screwfitting after filling. The stirred composition as well as thecomposition aliquots in the vials is protected from light.

Ultrasonication. Ultrasonication further reduces mean particle size. Inthis method the vials with the homogenised composition of the inventionare placed in an ultrasonication bath and sonicated for 2×10 minutes,whereupon the samples have an almost clear appearance in comparison withthe opaque composition afforded by Ultra-Turrax® homogenisation.

The aforementioned particle size reduction methods are compared in Table2. Particle size distribution was determined by laser diffraction(Mastersizer 2000, Malvern Instrument, UK). A Fraunhofer theory basedmethod was used to calculate the particle size of the high speedhomogenised sample whereas a MIE (2.50/0.001) theory based method wasused for calculation of the particle size of the sample additionallysubjected to sonication. TABLE 2 Particle size reduction (composition ofthe invention) Treatment Average size (nm) High speed homogenisation 940High speed homogenisation + 162 ultrasonication

EXAMPLE 2

TABLE 3 Batch formula of the composition of the invention Cetirizinedinitrate 2.22 mg Phospholipid (soybean; Lipoid S75; 7.00 mg LipoidGmbH, Germany) Citric acid, anhydrous 3.84 mg Sodium hydroxide, solid1.67 mg Ascorbic acid 0.20 mg EDTA sodium 0.20 mg HCl, 1 M and/or NaOH,1 M To pH 5.0 Water for injection To 200 mL

General procedure. For weights and volumes reference is made to Table 3.A buffer solution is prepared by dissolving anhydrous citric acid andsolid sodium hydroxide in 160 mL water (80% of the total batch volume)in a 200 mL volumetric flask. The weighed amount of active agent isadded and dissolved by stirring with a magnetic stirrer. Thephospholipid is separately weighed and added to the cetirizine solution.Stirring is continued until a well dispersed suspension has been formed,the pH of which is adjusted to pH 5.0±0.1 with 1.0 M NaOH and/or 1.0 MHCl. The volume of the preparation is then brought to the final batchvolume of 200 mL. The preparation is transferred to a high pressurehomogeniser (Rannie A P V, type 7.30 VH, Rannie A S, Denmark) andhomogenised at 500-800 bar for 5 cycles. Aliquots of the thus obtainedcomposition of the invention are removed from the collecting vessel andtransferred to glass vials.

In Table 4 the particle size reduction method is compared with highspeed homogenisation (Ultra Turrax® T25 homogeniser (Jankel & Kühnke,Germany), as described in Example 1. The composition described in thisexample has been used in both homogenisation methods. Particle sizedistribution was determined by dynamic light scattering (Zetasizer 4,Malvern Instruments, UK) at an angle of 90° and at room temperature,using a ZET5104 sizing cell and auto:CONTIN analysis mode. TABLE 4Particle size reduction (composition of the invention) Cetirizine Zaverage Treatment (mg/mL) mean (nm) High speed homogenisation 11.1 282High pressure homogenisation at 500 bar 11.1 77 High pressurehomogenisation at 800 bar 11.1 50 High pressure homogenisation at 500bar 0 130 High pressure homogenisation at 800 bar 0 121

The methods used for preparing these exemplary batch compositions wereadapted for preparing the following additional compositions of theinvention.

EXAMPLE 3

TABLE 5 Composition of the invention Cetirizine dinitrate 5.6 mgPhospholipid (soybean; Lipoid S75; Lipoid GmbH, 35.0 mg Germany)Disodium phosphate dihydrate; Na₂HPO₄.2H₂O 10.7 mg Potassium dihydrogenphosphate; KH₂PO₄ 5.5 mg 1 M HCl and/or 1 M NaOH To pH 7.0 Water forinjection To 1 mL

EXAMPLE 4

TABLE 6 Composition of the invention Cetirizine dinitrate 22.2 mgPhospholipid (soybean; Lipoid S75; 35.0 mg Lipoid GmbH, Germany)Disodium phosphate dihydrate; Na₂HPO₄.2H₂O 10.7 mg Potassium dihydroqenphosphate; KH₂PO₄ 5.5 mg 1 M HCl and/or 1 M NaOH To pH 7.0 Water forinjection To 1 mL

EXAMPLE 5

TABLE 7 Composition of the invention Cetirizine dinitrate 11.2 mgPhospholipid (soybean; Lipoid S75; Lipoid GrnbH, 70.0 mg Germany)Disodium phosphate dihydrate; Na₂HPO₄.2H₂O 10.7 mg Potassium dihydrogenphosphate; KH₂PO₄ 5.5 mg 1 M HCl and/or 1 M NaOH To pH 7.0 Water forinjection To 1 mL

EXAMPLE 6

TABLE 8 Composition of the invention Cetirizine dinitrate 11.1 mgPhospholipid (dioleoylphoshatidylcholine; DOPC, 35.0 Larodan FineChemicals, Sweden) Disodium phosphate dihydrate; Na₂HPO₄.2H₂O 10.7Potassium dihydrogen phosphate; KH₂PO₄ 5.5 1 M HCl and/or 1 M sodiumhydroxide To pH 7.0 Water for injection To 1 mL

EXAMPLE 7

TABLE 9 Composition of the invention Cetirizin dinitrate 11.1 mgPhospholipid (dioleoylphosphatidylglycerol; DOPG, 35.0 mg Avanti PolarLipids, AL, USA) Disodium phosphate dihydrate; Na₂HPO₄.2H₂O 10.7 mgPotassium dihydrogen phosphate; KH₂PO₄ 5.5 mg 1 M HCl and/or 1 M sodiumhydroxide To pH 7.0 Water for injection To 1 mL

EXAMPLE 8

TABLE 10 Composition of the invention Cetirizine dinitrate 11.1 mgGalactolipid (digalactosyldiacylglycerol; DGDG, 35.0 mg Larodan FineChemicals, Sweden) Disodium phosphate dihydrate; Na₂HPO₄.2H₂O 10.7 mgPotassium dihydrogen phosphate; KH₂PO₄ 5.5 mg 1 M HCl and/or 1 M sodiumhydroxide To pH 7.0 Water for injection To 1 mL

EXAMPLE 9

Nasal irritation test in a dog model. Cetirizine dinitrate (5.6, 11.1and 22.2 mg/mL, respectively, in the composition of EXAMPLES 1-3; nothomogenised) was administered twice daily for 14 days to four malebeagle dogs per group (5-6 months old, weighing 10.1-14.2 kg). Clinicalsigns and body weights were monitored throughout the study. A necropsywas performed, and the nasal cavity was collected and processed(fixated, decalcified and stained with haematoxylin and eosin). Foursections from the nasal cavity were evaluated microscopically, coveringsquamous, ciliated respiratory, and olfactory epithelium. Notreatment-related clinical signs were observed during the administrationperiod. The mean body weight gain over the administration period wasunremarkable. The macroscopic and microscopic examination of the nasalcavity and the nasal mucosa preparations did not reveal any signs ofmucosal irritation or other change.

EXAMPLE 10

Ocular irritation test in a rabbit model. The potential irritatingproperties of the phospholipid composition of the invention (EXAMPLE1-3) was also assessed in an eye irritation test in three white(albino), female New Zealand rabbits per treatment weighing between 2.8to 3.4 kg. The concentrations investigated were 5.6, 11.1 and 22.2 mg/mLin the composition of EXAMPLE 1. 0.1 mL of the composition was placed inthe left eye of each rabbit. The right eye served as untreated control.The eyes were examined prior to treatment and at 1, 24, 48, and 72 hafter treatment. The ocular reaction to treatment was graded accordingto a subjective numerical scoring system. Signs of conjunctivalirritation (redness) were observed in two rabbits in the group receivingthe composition containing 22.2 mg/mL cetirizine dinitrate. In the firstrabbit a score 2 (diffuse, crimson colour, individual vessels not easilydiscernable) on a scale graded 0-3 was noted one hour after treatment.In the second rabbit a score 1 (some hyperaemic blood vessels) on a fourgrade scale was noted at 24 h. In both cases the redness was not presentat subsequent observations, and was thus considered reversible. No othersigns of eye irritation were observed in any of the animals.

EXAMPLE 11

Nasal irritation test. A single dose (110 μL in each nostril) ofcetirizine dinitrate (11.1 mg/mL) was administered to five healthyvolunteers at four sessions in one of four formulations (I-IV) in eachsession. Formulations I, II, and III are formulations of the inventionwhereas reference formulation IV is not a formulation of the invention.The test was performed to investigate the reduction of irritation byliposome formulation as compared to plain buffer solution. Also theinfluence of particle size and the ratio phospholipid to cetirizine wasstudied. TABLE 11 Cetirizine dinitrate formulations used in testingnasal irritation mg Phospholipid Features per Formulation Composition mLVehicle Features I EXAMPLE 1 35 High speed homogenised II EXAMPLE 1 35High speed homogenised + ultrasonicated III EXAMPLE 5 70 High speedhomogenised + ultrasonicated IV Reference nil; Plain buffered aqueousphosphate solution buffer

Nasal symptom score were assessed at 1, 10, 30 minutes postadministration. The nasal symptom score included the followingvariables: nasal congestion, rhinorrhea, itching/sneezing, burning/pain,and taste. These symptoms were qualified by the subjects according to ano—mild—moderate—severe symptom scale (0-3). The results are reported astotal score, adding all five subjects scores (maximum score of 15).

The phospholipid formulations were better tolerated than the plainbuffer solution. Smaller liposomes seem to be of advantage. The milddiscomfort reported by all subjects at 1 minute had practicallydisappeared at 10 min for the two formulations (II and III) that hadreduced particle size by sonication. In contrast, the initial milddiscomfort reported for formulation I persisted at 10 minutes.Increasing the ratio of phospholipid to cetirizine did not furtherimprove the performance of the formulation. TABLE 12 Nasal irritationtest in healthy volunteers. Formu- Con- Itching/ Burning/ TOTAL lationgestion Rhinorrhea sneezing Pain Taste SCORE 1 min Post Administration I0 3 1 6.5 1 11.5 II 0 1 1 6.0 0 8 III 0 0 1 5.5 0 6.5 IV 0 6 2 14.5 224.5 10 min Post Administration I 0 1 1 6 4 12 II 0 0 0 2 2 4 III 0 0 11 4.5 6.5 IV 0 1 1 8 3 13 30 min Post Administration I 0 0 1 1 3 5 II 00 1 0 0 1 III 0 0 0 1 0 1 IV 0 0 0 1.5 1 2.5

EXAMPLE 12

Nasal irritation test. A single dose (110 μL in each nostril) ofcetirizine dinitrate (11.1 mg/mL) was administered to four healthyvolunteers at four sessions in one of four formulations (I-IV) in eachsession. The test was performed to investigate the irritative propertiesof formulations with different membrane lipids of natural and syntheticorigin. TABLE 13 Cetirizine dinitrate formulations used in testing nasalirritation Formulation Composition Membrane lipid I EXAMPLE 1 Lipoid S75Natural II EXAMPLE 6 Dioleoylphoshatidylcholine Synthetic (DOPC) IIIEXAMPLE 7 Dioleoylphoshatidylglycerol Synthetic (DOPG) IV EXAMPLE 8Digalactosyldiacylglycerol Natural (DGDG)

Nasal symptom score were assessed at 1, 10, 30 minutes postadministration. The nasal symptom score included the followingvariables: nasal congestion, rhinorrhea, itching/sneezing, burning/pain,and taste. These symptoms were qualified by the subjects according to ano—mild—moderate—severe symptom scale (0-3). The results are reported astotal score, adding all four subjects scores (maximum score of 12).

The formulations containing DOPC and DOPG were very well tolerated withpractically no reports of any kind at 1 minute. At 10 minutes there isstill a tendency of better tolerability of these two formulations ascompared to the membrane lipids of natural origin. TABLE 14 Nasalirritation test in healthy volunteers. Formu- Con- Itching/ Burning/TOTAL lation gestion Rhinorrhea sneezing Pain Taste SCORE 1 min PostAdministration I 0 1 1 3 2 7 II 0 1 0 1 0 2 III 1 0 1 0 0 1 IV 0 1.5 2 24 9.5 10 min Post Administration I 0 1 0 2 3 6 II 0 0 0 1 2 3 III 0 0.50.5 1 2 4 IV 0.5 0.5 0 1 4 6 30 min Post Administration I 1 0 0 0 0 1 II0 0 0 0 0 0 III 0 0 1 0 1 2 IV 0 0 0 0 0 0

1. Pharmaceutical composition for the treatment of rhinitis by nasal orocular administration comprising zwitterionic cetirizine, polar lipidliposome, a pharmaceutical acceptable aqueous carrier and, optionally, apharmaceutically acceptable buffer capable of providing a pH of from pH4.0 to pH 8.0, with the proviso that, if the polar lipid comprisesphospholipid, the amount of phospholipid in the composition is from 10mg per mL to 120 mg per mL.
 2. The composition of claim 1, wherein theamount of phospholipid is from 17 mg per mL to 120 mg per mL.
 3. Thecomposition of claim 1, wherein the amount of phospholipid is from 35 mgper mL to 70 mg per mL.
 4. The composition of claim 1, wherein said pHis from 5.0 to 7.0.
 5. The composition of claim 1, wherein thezwitterionic cetirizine has been obtained from a chloride or nitratesalt of cetirizine.
 6. The composition of claim 5, wherein the salt iscetirizine dinitrate.
 7. The composition of claim 1, wherein the bufferis selected from phosphate buffer, citrate buffer, acetate buffer. 8.The composition of claim 1 comprising cetirizine or a salt of cetirizinein an amount of from 1 mg/mL to 23 mg/mL calculated on the zwitterionicform.
 9. The composition of claim 1, comprising cetirizine or a salt ofcetirizine in an amount of from 5.5 mg/mL to 22 mg/mL.
 10. Thecomposition of claim 1 wherein the liposome is based on a phospholipidor on a mixture of phospholipids.
 11. The composition of claim 10,wherein the phospholipid is selected from the group consisting ofphosphatidylcholine, phosphatidylglycerol, phosphatidylinositol,phosphatidic acid, and phosphatidylserine
 12. The composition of claim10, wherein at least one phospholipid is of natural origin.
 13. Thecomposition of claim 10, wherein at least one phospholipid is ofsynthetic or semi-synthetic origin.
 14. The composition of claim 1,wherein the liposome is based on a glycolipid or a mixture ofglycolipids.
 15. The composition of claim 1, wherein the liposomeconsists of a glycolipid or a mixture of glycolipids.
 16. Thecomposition of claim 14, where the glycolipid is glycoglycerolipid. 17.The composition of claim 16, wherein the glycoglycerolipid comprisesgalactoglycerolipid.
 18. The composition of claim 16, whereinglycoglycerolipid comprises digalactosyldiacylglycerol.
 19. Thecomposition of claim 18, wherein glycoglycerolipid substantiallyconsists of digalactosyldiacylglycerol.
 20. The composition of claim 14,wherein the glycolipid is a glycosphingolipid.
 21. The composition ofclaim 14, wherein the glycolipid is a glycophosphatidylinositol.
 22. Thecomposition of claim 1 comprising at least one antioxidant, chelatingagent, preservative, or viscosity-increasing agent.
 23. A process forpreparing a pharmaceutical composition for the treatment of rhinitis bynasal or ocular administration comprising zwitterionic cetirizine, polarlipid liposome, a pharmaceutical acceptable aqueous carrier and,optionally, a pharmaceutically acceptable buffer capable of providing apH of from about pH 4 to about pH 8, with the proviso that, if the polarlipid comprises phospholipid, the amount of phospholipid in thecomposition is from 10 to 120 mg per mL, comprising (a) providing apolar lipid or a mixture of polar lipids that is swellable in aqueousmedia; (b) providing an aqueous solution of cetirizine and buffer havinga pH of from pH 4 to pH 8; (c) adding the polar lipid to the aqueoussolution while stirring, thereby forming a cetirizine liposomepreparation; (d) optionally adjusting the pH of the preparation to adesired value within the range of from pH 4 to pH 8 by adding an acid ora base; (e) optionally adding water or saline or a buffer having a pH offrom pH 4 to pH 8 to the preparation to obtain a desired final batchvolume; (f) homogenising the preparation to obtain said pharmaceuticalcomposition.
 24. The process of claim 23, wherein the amount ofphospholipid in the composition is from 17 to 120 mg per mL.
 25. Theprocess of claim 23, wherein the amount of phosphlipid in thecomposition is from 35 mg to 70 mg per mL.
 26. The process of claim 23,wherein the pH is from from pH 5.0 to pH 7.0.
 27. The process of claim23, wherein said mixture of swellable polar lipids has be pre-treatedwith organic solvent.
 28. The process of claim 23, whereinhomogenisation comprises at least one of vigorous mechanical mixing,shaking, vortexing, or rolling.
 29. The process of claim 22, additionalcomprising reduction of liposome size.
 30. The process of claim 29,wherein the reduction of liposome size comprises extrusion through amembrane filter or high-pressure homogenization or both.
 31. A methodfor the manufacture of a pharmaceutical composition for the treatment ofrhinitis comprising combining cetirizine and a pharmacologicallyacceptable liposomal carrier comprising polar lipid dispersed in anaqueous medium, with the proviso that, if the polar lipid comprisesphospholipid, the amount of phospholipid in the composition is from 10mg to 120 mg per mL.
 32. The method of claim 31, wherein the polar lipidis glycoglycerolipid.
 33. The method of claim 32, wherein theglycoglycerolipid comprises galactoglycerolipid.
 34. A method oftreating rhinitis comprising nasal administration of a pharmacologicallyeffective amount of the composition of claim
 1. 35. A method of treatingrhinitis comprising ocular administration of a pharmacologicallyeffective amount of the composition claim 1.